The present invention relates to new aromatic benzopyranyl and benzothiopyranyl compounds, to a process for their preparation and to their use in human or veterinary medicine and in cosmetic compositions.
These new compounds are usefully employed in the topical and systemic treatment of dermatologic diseases linked to a keratinization disorder (differentiation--proliferation) and dermatologic diseases (or others) having inflammatory and/or immunoallergic components and in the treatment of illnesses of the degeneration of conjunctive tissue. They also exhibit anti-tumor activity.
Moreover, these compounds can be employed in the treatment of atrophy, be it cutaneous or respiratory, and in the treatment of rheumatoid psoriasis.
These compounds also possess good activity against the germs involved in acne.
Finally, the compounds of the present invention are usefully employed in the opthamology field and principally in the treatment of corneopathies.
The aromatic benzopyranyl and benzothiopyranyl compounds of the present invention can be represented by the formula; ##STR5## wherein,
n is 0 or 1,
X represents ##STR6##
R' represents hydrogen, OH, alkoxy having 1-4 carbon atoms, acyloxy having 1-4 carbon atoms, or NH.sub.2,
R" represents hydrogen, or alkoxy having 1-4 carbon atoms,
or R' and R" together form an oxo radical (.dbd.O), a methano radical (.dbd.CH.sub.2) or a hydroxyimino radical (.dbd.N--OH),
R represents --CH.sub.2 OH or --COR.sub.8,
R.sub.8 represents hydrogen, ##STR7##
R.sub.9 represents hydrogen, linear or branched alkyl having 1-20 carbon atoms, mono or polyhydroxyalkyl, aryl or aralkyl optionally substituted, or the residue of a sugar or even the radical ##STR8##
p is 1, 2, or 3,
r" and r" each independently represent hydrogen, loweralkyl, monohydroxyalkyl optionally interrupted by a heteroatom, or polyhydroxyalkyl, aryl or benzyl optionally substituted, the residue of an aminoacid or an aminated sugar, or together form a heterocycle,
R.sub.1, R.sub.2, R.sub.3 and R.sub.4 each independently represent hydrogen or lower alkyl,
R.sub.5, R.sub.6 and R.sub.7 represent hydrogen or methyl, or when n=1, R.sub.5 and R.sub.7, taken together, form with the benzene ring a naphthalene ring (R.sub.5 -R.sub.7 =--CH=CH--),
and the salts of said compounds of formula I as well as their geometric and optical isomers.
By lower alkyl radical is meant an alkyl radical having 1-6 carbon atoms and principally methyl, ethyl, isopropyl, butyl and tert.butyl.
By monohydroxyalkyl is meant a radical having 2-6 carbon atoms and principally 2-hydroxy ethyl, 2-hydroxy propyl or 2-hydroxy ethoxyethyl.
By polyhydroxyalkyl is meant a radical containing 3-6 carbon atoms and 2-5 hydroxy groups such as 2,3-dihydroxy propyl, 1,3-dihydroxy propyl or the residue of pentaerythritol.
By aryl is meant phenyl optionally substituted by halogen, hydroxy, nitro, lower alkyl, --CF.sub.3 or --COOH.
By residue of an aminoacid is meant a residue derived, for example, from .alpha.- or .beta.-alanine or from methionine.
By residue of a sugar is meant a residue derived from, for example, glucose, mannose, erythrose or galactose.
By residue of an aminated sugar is meant a residue derived, for example, from glucosamine, galactosamine or mannosamine.
When the radicals r' and r" taken together form a heterocycle, the heterocycle is, preferably, piperidino, piperazino, morpholino, pyrrolidino or 4-(2-hydroxyethyl) piperazino.
When the compounds according to the present invention are provided in the form of salts, they can be salts of an alkali or alkaline earth metal or even of zinc, or of an organic amine when they carry at least one free acid function, or of salts of a mineral or organic acid, principally the hydrochloride, hydrobromide or citrate when they carry at least one amine function.
The preferred compounds of the present invention are those responding to formulas II and III below: ##STR9## wherein
n is 0 or 1,
X is ##STR10##
R' and R" taken together form an oxo radical, or R' represents hydroxyl and R" represents hydrogen,
R.sub.8 represents ##STR11##
R.sub.9 represents hydrogen or lower alkyl,
r' represents hydrogen, and
r" represents lower alkyl or a mono or polyhydroxyalkyl; and ##STR12## wherein
X represents --O-- or --S--,
R' and R" taken together form an oxo radical, or R' represents hydrogen or hydroxyl and R" represents hydrogen,
R.sub.1 and R.sub.2 each identically represent (i) methyl and in this case R.sub.3 and R.sub.4 represent hydrogen, or (ii) hydrogen, and in this case R.sub.3 and R.sub.4 represent methyl,
R.sub.8 represents hydrogen, ##STR13##
R.sub.9 represents hydrogen or lower alkyl,
r' represents hydrogen, and
r" represents lower alkyl or a mono or polyhydroxyalkyl radical.
The particularly preferred compounds of formula III above are those in which R.sub.1 and R.sub.2, identically represent methyl and R.sub.3 and R.sub.4 represent hydrogen.
Representative compounds of formula I, above, include the following:
(1) 4-(4,4-dimethyl-3,4-dihydro-6-benzopyranyl) carbonyl methyl benzoate, PA0 (2) 4-(4,4-dimethyl-3,4-dihydro-6-carbonyl benzoic acid, PA0 (3) N-ethyl-4-(4,4-dimethyl-3,4-dihydro-6-benzopyranyl) carbonyl benzamide, PA0 (4) 4-(4,4-dimethyl-3,4-dihydro-6-benzothiopyranyl) carbonyl methyl benzoate, PA0 (5) 4-(4,4-dimethyl-3,4-dihydro-6-benzothiopyranyl) carbonyl benzoic acid, PA0 (6) 4-(4,4-dimethyl-3,4-dihydro-1,1-dioxide-6-benzothiopyranyl) carbonyl benzoic acid, PA0 (7) 6-(4,4-dimethyl-3,4-dihydro-6-benzothicpyranyl) carbonyl 2-methyl naphthalene carboxylate, PA0 (8) 6-(4,4-dimethyl-3,4-dihydro-6-benzothopyranyl) carbonyl 2-naphthalene carboxylic acid, PA0 (9}N-ethyl-6-(4,4-dimethyl-3,4-dihydro-6-benzothiopyranyl) carbonyl 2-naphthalene carboxamide, PA0 (10) 6-(2,2-dimethyl-3,4-dihydro-6-benzopyranyl) carbonyl 2-methyl naphthalene carboxylate, PA0 (11) 6-(4,4-dimethyl-3,4-dihydro-6-benzopyranyl) carbonyl 2-methyl naphthalene carboxylate, PA0 (12) 6-(2,2-dimethyl-3,4-dihydro-6-benzopyranyl) carbonyl 2-naphthalene carboxylic acid, PA0 (13) 6-(4,4-dimethyl-3,4-dihydro-6-benzopyranyl) carbonyl 2-naphthalene carboxylic acid, PA0 (14) N-ethyl-6-(4,4-dimethyl-3,4-dihydro-6-benzopyranyl) carbonyl 2-naphthalene carboxamide, PA0 (15) N-ethyl-6-(4,4-dimethyl-3,4-dihydro-6-benzopyranyl) hydroxymethyl 2-naphthalene carboxamide, PA0 (16}6-(4,4-dimethyl-3,4-dihydro-6-benzopyranyl) hydroxymethyl 2-naphthalene carbinol, PA0 (17) 6(4,4-dimethyl-3,4-dihydro-6-benzopyranyl) carbonyl 2-formyl naphthalene, PA0 (18) trans 4-(4,4-dimethyl-3,4-dihydro-6-benzopyranyl) carbonyl ethyl .alpha.-methyl cinnamate, PA0 (19) trans 4-(4,4-dimethyl-3,4-dihydro-6-benzopyranyl) carbonyl .alpha.-methyl cinnamic acid PA0 (20) N-ethyl trans 4-(4,4-dimethyl-3,4-dihydro-6-benzopyranyl) carbonyl .alpha.-methyl cinnamide, PA0 (21) trans 4-[(4,4-dimethyl-3,4-dihydro-6-benzothiopyranyl) hydroxymethyl] ethyl .alpha.-methyl cinnamate, PA0 (22) trans 4-[(4,4-dimethyl-3,4-dihydro-6-benzothiopyranyl) hydroxymethyl] .alpha.-methyl cinnamic acid, PA0 (23) trans 4-(4,4-dimethyl-3,4-dihydro-6-benzothiopyranyl) carbonyl .alpha. methyl cinnamic acid, PA0 (24) 6-[(4,4-dimethyl-3,4-dihydro-6-benzopyranyl) hydroxymethyl] 2-napthalene carboxylic acid, PA0 (25) 4-(4,4-dimethyl-3,4-dihydro-6-benzothiopyranyl) hydroxymethyl methyl benzoate, PA0 (26) 4-[(4,4-dimethyl-3,4-dihydro-6-benzothiopyranyl) hydroxymethyl]benzoic acid and PA0 (27) 1-(4,4-dimethyl-3,4,-dihydro-6-benzopyranyl)-1-(6-carboxy-2-naphthyl) methane.
The particularly preferred compounds of those listed above are the following ones:
6-(4,4-dimethy-3,4-dihydro-6-benzopyranyl) carbonyl 2-naphthalene carboxylic acid and 6-(4,4-dimethyl-3,4-dihydro-6-benzothiopyranyl) carbonyl 2-naphthalene carboxylic acid, and their esters and amides, as well as 1-(4,4-dimethyl-3,4-dihydro-6-benzopyranyl)-1-(6-carboxy-2-naphthyl) methane.
The present invention also relates to a process for preparing the compounds of formula I in accordance with the following reaction scheme: ##STR14##
The chloride of 4-alkoxy carbonyl-2-benzoic acid (2) is obtained starting with an alkyl paraformyl benzoate which is oxidized in a corresponding acid using a Jones reactant, then transformed into the acid chloride by the action of thionyl chloride in accordance with known methods for the preparation of acid chlorides.
The chloride of 6-alkoxy carbonyl-2-naphthalene carboxylic acid (3) is obtained by the reaction of thionyl chloride with 6-alkoxy carbonyl-2-napthalene carboxylic acid resulting from the monosaponification reaction of 2,6-alkyl naphthalene dicarboxylate (a commercial product}.
The substituted derivatives of chroman and thiochroman, principally the 2,2-dimethyl derivatives (compound of formula (1) with X.dbd. --O-- or --S--, R.sub.1 =R.sub.2 .dbd.H and R.sub.3 .dbd.R.sub.4 =CH.sub.3) and the 4,4dimethyl derivatives (compound of formula (1) with X.dbd. --O-- or --S--, R.sub.1 =R.sub.2 .dbd.CH.sub.3 and R.sub.3 .dbd.R.sub.4 .dbd.H) are prepared by the method described in J. Med. Chem. (1984) 27, 1516-1531.
The condensation reaction of the chloride of 4-alkoxycarbonyl-2-benzoic acid (2) or of the chloride of 6-alkoxycarbonyl-2-naphthalene carboxylic acid (3) on the chroman or thiochroman, optionally substituted, (1) is carried out under conventional Friedel-Crafts reaction conditions, i.e., in the presence of anhydrous aluminum chloride or anhydrous stannous chloride in 1,2-dichloroethane at a temperature between 0.degree. and 25.degree. C. with stirring.
Starting with the keto-ester (Ia) there is obtained by saponification the corresponding ketoacid (Ib) which can then be transformed into the amide of formula (Ic) by reaction with an amine of the formula ##STR15## (r' and r" having the meanings given above) in the presence of N, N'-carbonyldiimidazole (CDI).
When R.sub.9 represents a monohydroxy or polyhydroxy alkyl radical, it is preferred to prepare the keto-acid (Ib) starting with the methyl ester (Ia) R.sub.9 .dbd.CH.sub.3) and then esterify the resulting keto-acid into the keto-ester of the mono or polyhydric alcohol selected in accordance with known procedures.
Starting with the keto-acid (Ib), the reduction by sodium borohydride in an organic solvent such as THF leads to the secondary alcohol (Id) and the reduction by lithium aluminum hydride of the keto-acid (Ib) leads to the diol (Ie).
On oxidation of the diol (Ie) by pyridinium chlorochromate (PCC) the keto-aldehyde (If) results.
The keto-aldehydes (If) in which n=O constitute starting products for the synthesis of the compounds of formula I wherein n.dbd.1 and R.sub.5 -R.sub.7 .noteq.--CH.dbd.CH--.
These compounds are obtained according to the following reaction scheme: ##STR16##
The Wittig-Horner reaction of the keto-aldehyde (If) with phosphono-acetate, substituted or not, is carried out in the presence of sodium hydride in an organic solvent such as THF.
The resulting unsaturated keto-ester (Ig) can then be transformed, as before, into the corresponding acid, then into the amide by reaction with an amine of the formula ##STR17## or can be reduced by sodium borohydride into a corresponding primary alcohol.
The hydroxyacids of formula (Id) and the corresponding hydroxy esters of formula (I'd), for which n.dbd.1, and R.sub.5 .dbd.R.sub.6 .dbd.H can be obtained by reacting, an organomagnesium compound prepared from the brominated derivative (2) in position 6 with a -formyl alkyl cinnamate (3) in accordance with the following reaction scheme: ##STR18##
The formyl alkyl cinnamates (3) are obtained from commercial terephthaldehyde (4), one of the aldehyde functions being protected in the form of dimethylhydrazone. The aldehyde (5) thus obtained is then condensed on an alkyl phosphonoacetate under the Wittig-Horner reaction conditions and the protected aldehyde function is then freed in an acid medium by exchange with glyoxal to obtain a p-formyl alkyl cinnamate (3). ##STR19##
The compounds of formula I, wherein R'.dbd.R".dbd.H, are obtianed by the zinc reduction of ketonic derivatives in acetic acid in the presence of HCl. These reduction reactions of the carbonyl must, however, be compatible with the nature of the R and X radicals. It can be desirable to ensure the optional protection, however the reduction of the carbonyl creates no difficulty when R.dbd.CO.sub.2 H and X.dbd.--O--or --S--.
The acyloxy derivatives of the compounds of formula I (R'.dbd.C.sub.1 -C.sub.4 acyloxy and R".dbd.H) are obtained by reacting an activated acid form, such as an anhydride or acid chloride with a compound of formula I wherein R'.dbd.OH and R".dbd.H.
The alkoxy derivatives of the compounds of formula I (R'.dbd.C.sub.1 -C.sub.4 alkoxy and R".dbd.H) are also obtained starting with compounds of formula I (R'.dbd.OH and R".dbd.H) in accordance with known methods.
For the preparation of the acyloxy and alkoxy derivatives it is preferable that the radical R is an ester, acid or amide function.
The present invention further relates to a medicine comprising the compounds of formula I as defined above.
These compounds exhibit excellent activity in the inhibition test of ornithine decarboxylase in nude rats, after induction, by "tape stripping," M. Bouclier, et al, Dermatologica 169, No.4 (1984). This test is recognized as a measure of an antiproliferative activity.
These compounds are particularly appropriate for treating dermatologic ailments linked to a keratinization disorder (differentiation-proliferation) as well as dermatologic diseases, or others, having an inflammatory and/or immunoallergic component, principally:
acne vulgaris, comedons or polymorphs, solar senile acne and medicinal or professional acne,
extensive and/or severe forms of psoriasis and other keratinization disorders, and principally ichtysoses and ichtysosis like conditions,
Darier malady,
palmo-plantar keratodermies,
leucophasies and leucophasie-like states, lichen plan,
all malignant or benign dermatologic proliferations, severe or extensive.
They are also active in the treatment of tumors, of rheumatoid psoriasis, cutaneous or respiratory atrophies as well as in certain opthalomogic problems relating to corneopathies.
Thus, the present invention also relates to medicinal compositions containing at least one compound of formula (I), such as defined above, or one of its salts or one of its isomers.
The present invention thus relates to a new medicinal composition, intended principally for the treatment of the above-mentioned disorders, comprising in a pharamaceutically acceptable support, an effective amount of at least one compound of formula (I) and/or one of its salts and/or one of its isomers.
The compounds according to the present invention are generally administered at a daily dosage of about 0.01 .mu.g/kg to 1 mg/kg of body weight.
As the vehicle or carrier for these compositions any conventional vehicle can be employed, the active component being found either in the dissolved state, or in the dispersed state in said vehicle.
The administration of the compounds of the present invention can be effected enterally, parenterally, topically or ocularly.
When administered enterally, the medicines can be provided in the form of tablets, gelules, lozenges, syrups, suspensions, solutions, powders, granules or emulsions.
When administered parenterally, the medicinal compositions can be provided in the form of solutions or suspensions for perfusion or injection.
When administered topically, the pharmaceutical compoitions, based on the compounds according to the present invention, can be provided in the form of ointments, tinctures, creams, salves, powders, pads, impregnated tampons, solutions, lotions, gels, sprays or suspensions.
These compositions for topical administration can be provided under anhydrous form or in aqueous form according to clinical indications.
When administered ocularly, the composition is provided principally in the form of an eyewash.
The compositions for topical or ocular administration contain preferably from 0.0001 to about 5 percent by weight of at least one compound of formula (I) such as defined above, and preferably from 0.001 to 1 percent by weight, relative to the total weight of the composition.
The compounds of formula (I), according to the present invention, are also useful in the cosmetic field, in particular in body and hair hygiene compositions and principally for the treatment of skin having acne tendencies, to improve the growth of hair, to combat hair loss, to combat against an oily appearance of the skin or hair, in the prevention or treatment of the harmful effects of the sun or in the treatment of physiologically dry skin.
The present invention thus relates to a cosmetic composition containing, in a cosmetically acceptable vehicle, an effective amount of at least one compound of formula (I) or one of its salts and/or one of its isomers, this composition being provided principally in the form of a lotion, gel, cream, soap or shampoo.
The concentration of the compound of formula (I) in these cosmetic compositions is between 0.0001 and 2 percent by weight and, preferably, between 0.001 and 1 percent by weight based on the total weight of the composition.
The medicinal and cosmetic compositions according to the present invention can contain inert or even pharmacodynamic or cosmetically active additives and, principally: hydrating agents such as thiamorpholinone and its derivatives or urea; antiseborrheic or anti-acne agents such as S-carboxymethylcysteine, S-benzylcysteamine, their salts and their derivatives, tioxolone or benzoyl peroxide; antibiotics such as eythromycin and its esters, neomycin, tetracyclines and 4,5-polymethylene-3-isothiazolones; agents promoting the growth of hair such as "Minoxidil" (2,4-diamino-6-piperdino-3-pyrimidine oxide) and its derivatives, Diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine-1,1-dioxide) and Phenytoin (5,5-diphenyl-2,4-imidazolidine dione); steroidal and non-steroidal anti-inflammatory agents; carotenoids and, principally, .beta.-carotene; anti-psoriasic agents such as anthralin and its derivatives and 5,8,11,14 -eicosatetraynoic and 5,8,11-eicosatriynoic acids, their esters and their amides.
The compositions according to the present invention can also include flavor improving agents, preservatives, stabilizers, humidity regulating agents, pH regulating agents, osmotic pressure modifying agents, emulsifiers, UV-A and UV-B filters, anti-oxidants such as .alpha.-tocopherol, butylhydroxyanisole or butylhydroxytoluene
The following non-limiting examples illustrate the preparation of the active compounds of formula (I) according to the present invention as well as compositions containing these compounds.